We have developed a urinary message for nephrin (UMN) assay that sensitively and specifically detects loss of podocytes in a number of disorders, including, type 1 diabetes. We propose to use this test to determine the usefulness of UMN for early detection and monitoring the therapy of complications associated with diabetes type 1. The test uses the finding of nephrin mRNA in the urine to determine that podocytes are being lost abnormally in the kidney. Podocytes are the crucial cells that separate the blood and urine streams. Since UMN anomalies antecede albuminuria, UMN has the potential to serve as an early warning that diabetic nephropathy is occurring permitting earlier institution of therapy. Further, UMN anomalies can persist during therapy, suggesting that UMN determinations may be useful to evaluate therapy. We will test the usefulness of the UMN assay in three ways: 1.We will continue and conclude studies on longitudinal Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications type 1 diabetes samples to investigate whether UMN anomalies are harbingers of future kidney or retinal disease. 2. We will determine whether angiotensin converting enzyme inhibitor (ACEI) therapy can decrease UMN values before albuminuria is seen. This will be done by taking subjects with elevated UMN but no albuminuria and randomizing them into groups that are treated or untreated with an ACEI. The goal will be to determine whether ACEI therapy can lower abnormal elevations of UMN, supporting the concept of treating individuals with abnormal UMN but normoalbuminuria. 3. Since a majority of albuminuric subjects on ACEIs or angiotensin 2 receptor blockers (ARBs) show normally low values of UMN, we aim to evaluate whether the individuals with elevated UMN are those in whom drug therapy is ineffective. This will be accomplished by longitudinal studies of normotensive type 1diabetic individuals on ACEI or ARB therapy. In addition, we will compare UMN values in subjects with type 1 diabetes on ACEIs or ARBs who have not developed kidney disease with those who have known chronic renal insufficiency (CRI). Evidence for drug effectiveness will thus be compared directly with UMN values in these 2 populations.